FI92825B - Process for the preparation of therapeutically useful chromane derivatives - Google Patents

Description

92825

A process for the preparation of therapeutically useful chromium derivatives

The invention relates to a process for the preparation of therapeutically useful chromium derivatives of the formula I

R® R5-Z, yR4R8 10 ^ 3 ^ ot "R2 1 R7 wherein R1 and R2 are each independently A, R1 and R2 may also together be alkylene having 3 to 6 carbon atoms, R3 is OH or O-COA , R * is H, R3 and R4 together also denote a bond, R5 is an unsubstituted or A- or OH-substituted pyridyl, pyridazinyl, pyrazinyl, oxodihydropyridyl or oxodihydropyridazinyl radical, R6 is AOOC, NO2 or CN, R 7 and R 8 are hydrogen, Z is O or S, and A is alkyl of 1 to 4 carbon atoms, and pharmaceutically acceptable acid addition salts thereof.

The object of the invention was to find new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.

It was found that the compounds of the formula I and their physiologically acceptable salts, in addition to good tolerability, have valuable pharmacological properties. Thus, they appear to have effects on the cardiovascular system, with generally, at lower doses, a selective target effect on the coronary system can be observed, at higher doses an antihypertensive effect. In the coronary system, for example, there is a decrease in resistance and an increase in flow, whereby the effect of 5-cell on the heart rate remains small. In addition, the compounds appear to have a relaxing effect on various smooth muscle organs (gastrointestinal tract, respiratory system and uterus). The effects of the compounds can be determined by known methods described, for example, in EP-A1-76075, EP-A1-173848 or AU-A-45547/85 (Derwent Farmdoc No. 86081769) as well as in K.S. Meesmann et al., Arzneimittelforschung 25 (11), 1975, 1770 - 1776. Suitable experimental animals are e.g.

mice, rats, guinea pigs, dogs, cats, monkeys or pigs.

The compounds can therefore be used as active pharmaceutical ingredients in human and veterinary medicine. Furthermore, they can be used as intermediates for the preparation of other active pharmaceutical ingredients.

In said formulas, A preferably represents 20 non-side chain alkyl groups having 1 to 4, in particular one, two or three C atoms, in particular primarily methyl, further preferably ethyl, propyl, isopropyl, butyl, isobutyl, further preferably sec-butyl and tert butyl. v When R 1 and R 2 together represent alkylene, the alkylene group is preferably non-side chain, in detail preferably - (CH 2) n -, where n is 3, 4, 5 or 6.

R1 and R2 are in each case preferably alkyl, in particular in each case methyl or ethyl, in each case in each case methyl; further R 1 and R 2 together are preferably - (CH 2) 4 - or - (CH 2) 5 -.

When R 4 is H, R 3 is primarily OH, further preferably O-COCH 2.

R 5 is preferably 6-hydroxy-3-pyridazinyl (= 1,6-dihydro-6-oxo-3-pyridazinyl) or 2-hydroxy-4 - «

II

92825 3 pyridyl (= 1,2-dihydro-2-oxo-4-pyridyl), further preferably unsubstituted 2-, 3- or 4-pyridyl, 3-, 4- or 5-pyridazinyl or pyrazinyl, hydroxypyridyl such as 3-, 4-, 5- or 6-hydroxy-2-pyrid-5-yl, 2-, 4- or 5-hydroxy-3-pyridyl, 3-hydroxy-4-pyridyl, 2-hydroxy-5-pyridyl; hydroxypyridazinyl such as 4- or 5-hydroxy-3-pyridazinyl, 3-, 5- or 6-hydroxy-4-pyridazinyl; hydroxypyrazinyl such as 3-, 5- or 6-hydroxy-2-pyrazinyl; dihydroalkyloxo-10 pyridyl such as 1,2-dihydro-1-methyl-2-oxo-3-, -4-, -5- or -6-pyridyl, 1,2-dihydro-1-ethyl-2-oxo-3 -, -4-, -5- or -6-pyridyl; dihydroalkyloxopyridazinyl such as 1,6-dihydro-1-methyl-6-oxo-3-, -4- or -5-pyridazinyl, 1,6-dihydro-1-ethyl-6-oxo-3-, -4- or -5-pyri-15 dazinyl.

Those groups R5 having a hydroxy group adjacent to the ring N atom may also be in the tautomeric form of the lactam as indicated in the individual cases above.

In R6, A00C primarily denotes methoxycarbon-20-yl, including ethoxycarbonyl.

The group R6 is primarily in the 6-position of the chroman system. However, it can also be in the 5-, 7-, and 8-positions. R6 is primarily CN or NO2.

Accordingly, the invention relates in particular to the preparation of compounds of the formula I in which at least one of said groups has one of the abovementioned primary meanings. Some preferred groups of compounds may be expressed by the following formulas Ia to III, which correspond to formula I and in which the undisclosed groups have the meaning given in connection with formula I, however,

In Ia, R1 and R2 in each case denote A;

In Ib, Rx and R2 in each case denote CH3;

In Ic, R 1 and R 2 together represent alkylene if -35a has 3 to 6 C atoms; 92825 4

In Id, R5 represents an unsubstituted or OH-substituted pyridyl, pyridazinyl or pyrazinyl group or an Ally substituted oxodihydropyridyl or oxodihydropyridazinyl group; In these 5, R 5 represents 2-hydroxy-4-pyridyl or 6-hydroxy-3-pyridazinyl;

In R 5 represents 6-hydroxy-3-pyridazinyl;

In Ig1, R1 and R2 in each case denote CH3 or together the group - (CH2) 4- or - (CH2) 5-; R5 represents an unsubstituted or OH-substituted pyridyl, pyridazinyl or pyrazinyl group or an Ally substituted oxodihydropyridyl or oxodihydropyridazinyl group;

In humans, R1 and R2 in each case denote CH3; R 5 mer-15 contains 2-hydroxy-4-pyridyl, 6-hydroxy-3-pyridazinyl or 1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl and Z is 0;

In each case, R1 and R2 in each case denote CH3; R 5 is 6-hydroxy-3-pyridazinyl and Z is 0.

20 Preferred further are the compounds of formulas 1 'and Ia' - li 'corresponding to formulas I and

Ia-li, in which case, in addition, R3 is in each case OH or OCOCH3, in particular those compounds of the formulas 1 'and Ia' - li 'in which in each case R3 is in addition OH.

·. Further preferred are compounds of formulas 1 '' and Ia '' - «li '' corresponding to formulas I and Ia to II, in which, however, in each case R3 and R4 together also represent a bond.

Also preferred are compounds of formulas I, I ', I' ', Ia-30 li, Ia' - li 'and Ia' '- li' ', wherein in each case further (a) R 6 is in the 6-position; (b) R 6 is NO 2, CN, CH 3 OC or C 2 H 5OOC; (c) R 6 is NO 2, CN, CH 3 OC or C 2 H 5 OC and is in the 6-position; s 92825 (d) R 6 is NO 2 or CN; (e) R 6 is NO 2 or CN and is in the 6-position; (f) R 6 is CN; (g) R 6 is in the CN and 6-position.

5 Otherwise, in the above and in the following groups R1 to R8 and A, have the meanings given in connection with formula I, unless expressly stated otherwise.

The process according to the invention for the preparation of chromium derivatives of the formula I is characterized in that the chromane of the formula II

R

wherein XY is -CH-CR8- or -CHE-CR3R8- and E is Cl, Br, I or a reactive esterified OH group and R1, R2, R3, R6, R7 and R8 are as defined in formula I, is reacted with a compound of formula III • 25

R5-ZH III

wherein R 5 and Z 1 have the meanings given in connection with the formula I, or with a reactive derivative thereof, and / or a compound of the formula I in which R 3 is OH and R 4 is H is dehydrated and / or acylated in the compound of the formula I hydroxy group, and in the compound of formula I, the secondary nitrogen atom of the heterocyclic ring is alkylated, 6,92825 and / or the basic compound of formula I is converted by acid treatment into a pharmaceutically acceptable acid addition salt.

The compounds of formula I are generally prepared by known methods described in the literature (e.g. in standard works such as Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York as well as in the above-mentioned patent applications), and under reaction conditions known and suitable for said reactions. In this case, known variants, which are not mentioned in more detail here, can also be used.

If desired, the starting materials can be formed in situ so that they are not isolated from the reaction mixture, but are immediately reacted further to give compounds of formula I.

Preferably, compounds of formula I are prepared by reacting compounds of formula II with compounds of formula III, conveniently in the presence of an inert solvent at temperatures between about 0 and 150 ° C.

Preferred are the starting materials of formula II, wherein X-Y = -CH-CR8- (3,4-epoxychromanes).

The starting materials II and III are generally known (cf. e.g. DE-OS 3 726 261). If they are not known, they can be prepared by known methods. Thus, starting materials of formula Λ 8 30 II (-XY- * -CH-CR8-) can be obtained by reacting 2-hydroxyacetophenones of formula 2-HO-R6R7C6H2-COCH3 with ketones of formula R1-CO-R2 to the corresponding 4-chromanones of formula IVa «

II

92825 7 r6 IVa -XY- = -CO-CH2- IVb -XY- = -CO-C (= CH-R9) - Γ II T R2 IVc -XY- = -CHOH-CHR8- 5 0 '\ R1 IVd - XY- = -CH = CR8- R7 IVe -XY- = -CHBr-CR8OH- optionally by condensing with aldehydes of formula R9-CHO (R9 = alkyl of 1 to 5 carbon atoms) to give 3-b of formula IVb. alkylidene-4-chromanones, by reduction with e.g. NaBH4 to chromanols of formula IVc, dehydration with e.g. p-toluenesulfonic acid to chromenes of formula IVd and oxidation, e.g.

With 3-chloroperbenzoic acid. The latter oxidation 15 can also take place in several stages. Thus, for example, with N-bromosuccinimide in aqueous solution, bromohydrins of the formula IVe can first be prepared and these can then be cleaved with a base, e.g. with sodium hydroxide solution, HBr.

Chromenes of formula IVd can also be obtained by condensing salicylaldehydes of formula 2-HO-R6R7-C6H2-CHO with ketones of formula R1-CO-CH2-R8 to hydroxyl ketones of formula 2-HO-R6R7C6H2-CH = CR8-CO-R1. by reacting with organic Li compounds of formula R2-Li and then hydrolyzing them to diols of formula 2-HO-R6R7C6H2-CH = CR8-CR1R2-OH and cyclizing by cleavage of water.

Suitable compounds of the formula II (-XY- = -CHE-CR3R8-) as "reactive esterified OH groups" are in particular esters with alkylsulfonic acids (having 1 to 6 carbon atoms in the alkyl group) or with arylsulfonic acids (having 6 aryl groups in the aryl group). -10 C atoms). These compounds are obtained from the 4-chromanols of formula IVc by reaction with an inorganic acid halide such as PCl 3, PBr 3, SOCl 2 or SO 2 Br 2, or a sulfonic acid chloride such as methane or p-toluenesulfonic acid chloride.

8,92825

Suitable salts for the reactive derivatives of the formula III are, for example, the Na or K salts, which can also be formed in situ.

It is expedient to carry out the work in the presence of base 5. Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, carbonates, -alcoholates, hydrides or also amides, such as NaOH, KOH, Ca (OH) 2, Na2CO3, K2CO3, Na- or K-methylate, -ethylate or tert-butylate, NaH, KH, CaH2, NaNH2, KNH2, further organic bases such as triethylamine or pyridine, which can also be used in excess and thus act simultaneously as solvent.

Suitable inert solvents are, in particular, alcohols, such as methanol, ethanol, isopropanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ethers (diglyme); ketones such as acetone or butanone; nitriles such as acetonitrile; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; amides such as dimethylformamide (DMF), dimethylacetamide or phosphoric acid hexamethyltriamide; sulfoxides such as dimethyl sulfoxide (DMSO); chlorinated carbohydrates such as dichloromethane, chloroform, trichlorethylene, 1,2-dichloroethane or carbon tetrachloride; hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents are still suitable.

Λ.

Epoxide II (X-Y = -CH-CR-) can also be prepared in situ, e.g. by allowing a base to act on the corresponding bromohydrin IVe.

One particularly preferred mode of operation is based on the use of an alcohol (e.g. ethanol) 35 as the solvent and the addition of an organic base (e.g. pyridine), suitably boiling for about 0.5 to 20 hours.

«9»

II

92825 9

A compound of formula I wherein R 3 = OH and R 4 = H can be converted by treatment with a dehydrating agent to a compound of formula I wherein R 3 and R 4 together represent a bond. It is possible, for example, under the action of one of said 5 bases, e.g. NaH, in one of said solvents, e.g. in DMSO, at temperatures between 0 and 150 ° C. In particular, compounds where Z = S can be dewatered in this way.

Furthermore, in the compound of formula I, the hydroxy-10 group can be acylated.

The primary or secondary amino group can be converted to the corresponding secondary or tertiary amino group by treatment with alkylating agents. Suitable alkylating agents are, for example, the compounds of the formulas A-Cl, A-Br and A-I or the corresponding sulfuric acid or sulfonic acid esters, such as methyl chloride, bromide, iodide, dimethyl sulfate, methyl p-toluenesulfonate. The alkylation is conveniently carried out in the presence or absence of one of said inert solvents, e.g. DMF, at temperatures between about 0 and about 120 ° C, in which case a catalyst, preferably a base such as potassium tert-butylate or NaH.

Suitable acylating agents for the acylation of hydroxy groups are suitably halides (e.g. chlorides or bromides) or carboxylic acid anhydrides of the formula Ac-OH, e.g. acetic anhydride, propionyl chloride, isobutyryl bromide, formic acid, formic acid, formic acid The addition of a base such as pyridine or triethylamine during acylation is possible. The acylation is conveniently carried out in the presence or absence of an inert solvent such as a hydrocarbon such as toluene, a nitrile such as acetonitrile, an amide such as DMF or an excess of a tertiary base such as pyridine or triethylamine at temperatures between about 0 ° C and 160 ° C. primarily between> * 1 10 92825 at 20 and 120 ° C. Formylation is also possible with formic acid in the presence of pyridine.

The base of formula I can be converted with an acid into its acid addition salt. In this reaction, acids which form physiologically harmless salts are particularly suitable. Thus, inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, organic acids above, especially aliphatic, aliphatic, aricyclic, alicyclic, aricyclic, polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid-15a, succinic acid, pimelic acid, fumaric acid, ma le! succinic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, nicotinic acid, isonicotinic acid, methanoic acid, methane or ethanesulfonic acid , benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically acceptable acids, e.g. picrates, can be used with the compounds of the formula I; 25 den for cleaning.

The compounds of formula I may have one or more centers of rotation. They can therefore be prepared in the form of racemates or, if optically active starting materials are used, also in optically active form. If the compounds have two or more centers of rotation, then they can be obtained in the synthesis as mixtures of racemates, from which the individual racemates, for example by recrystallization from inert solvents, can be isolated in pure form. Thus, for example, in compounds of formula I 35 in which R1 = R2, R3 = OH and R4 = H, 1

II

»92825 11 has two rotation centers; however, in the preparation of the reaction of compound II with compound III, only a racemate is formed, which in the trans position is completely predominantly. The racemates obtained can, if desired, be separated mechanically, chemically or from their biochemical enantiomers by known methods.

Thus, the racemate can be formed by reacting diastereomers with an optically active resolving agent. Suitable resolving agents for the basic compounds of the formula I are, for example, optically active acids, such as the D and L forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, camphoric acid, camphorsulfonic acid, mandelic acid, malic acid or lactic acid. Furthermore, carbinols (I, R 3 = OH) can be esterified with circulating acylating reagents, e.g. of said acids, in particular (+) - or (-) - camphoric acid or (+) - or (-) - camphor-10-sulpho- with nitric acid or D- or La-methylbenzyl isocyanate, and then separated (cf. EP-A1-120428). The various forms of the diastereomers can be separated by known methods, e.g. fractional crystallization, and the enantiomers of the formula I can be liberated from the diastereomers in a known manner. Separation of the enantiomers is further achieved by chromatography on optically active supports.

The compounds of the formula I and their physiologically acceptable salts can be used for the preparation of pharmaceutical preparations, in particular non-chemical routes. In this case, they can be combined with at least one solid, liquid and / or semi-liquid carrier or excipient and optionally in combination with one or more other active ingredient (s) in a suitable dosage form.

These preparations can be used as drugs in human and veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for internal (e.g. oral), parenteral or topical application 92825 12 and which do not react with new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol tri-acetate , gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petrolatum. Particularly suitable for oral use are tablets, granules, capsules, syrups, juices or drops, suppositories for anal use, solutions for parenteral use, primarily oily or aqueous solutions, further suspensions, emulsions or implants, ointments, creams, pastes for topical use, washing liquids, gels, sprays, foams, aerosols, solutions (e.g. solutions in alcohols such as ethanol or iso-propanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol or mixtures thereof and / or with water) or powders. The novel compounds can also be lyophilized and the lyophilizates prepared can be used, for example, for the preparation of injection preparations. Liposomal preparations are also suitable, especially for topical use. Said preparations may be sterilized and / or may contain adjuvants such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts of osmotic agents; 25 to adjust its pressure, buffers, colorants, flavors and / or flavors. If desired, they may also contain one or more other active ingredients, e.g. one or more vitamins.

The compounds of the formula I and their physiologically acceptable salts can be administered to humans or animals, in particular mammals, such as monkeys, dogs, cats, rats or mice, and used in the therapeutic treatment of the human or animal body and in the control of diseases, in particular and / or in the prevention of cardiovascular disorders, • · «92825 13 in particular heart failure, convulsions, irregularities in the heart, peripheral or cerebrovascular diseases, as well as conditions associated with hypertension, further diseases associated with musculoskeletal disorders, asthma, bladder incontinence.

In this case, the substances according to the invention are generally administered in the same manner as known anti-throat agents or antihypertensive agents, e.g.

Nicorandil or Cromakalim, preferably in doses ranging from about 0.1 to 5 mg, especially from 0.02 to 0.5 mg per dosage unit. The daily dose is preferably between about 0.0001 and 0.1, in particular between 0.0003 and 0.01 mg per kilogram of body weight. However, the specific dose for each particular patient depends on various factors, such as the efficacy of a particular compound used, age, body weight, general health, sex, diet, time and route of administration, slag secretion rate, drug-20 combination, and disease severity. affected by the treatment. Oral administration is the primary route.

The compounds of the formula I and their salts are still suitable, in particular for topical application, for the treatment of baldness. For this purpose, various pharmaceutical preparations suitable for the topical treatment of the scalp and mentioned above are used. They contain from about 0.005 to 10%, preferably from 0.5 to 3% by weight, of at least one compound of the formula I and / or at least one of its salts. In general, these compounds 30 can be used against echo in the same manner as disclosed in WO 88/00822.

Pharmacological test results

The antihypertensive effect of the compounds of the invention was measured spontaneously in hypertensive rats just before oral administration of test compounds and 120 minutes after oral administration of 1 mg test compound / kg body weight. Test compounds were administered via gavage suspended in 5% aqueous gum arabic.

5

The compounds of formula I (r1 = r2 = methyl, R4 = R7 = R8 = H) have a blood pressure of 10 m.p. R3 R5-Z R6 neen alenem.

° C (mmHg) 164 OH 1,6-dihydro-1-methyl-6-CN-151 6-oxo-3-pyridazinyloxy [(-) - enantiomer] 229 OH 1,6-dihydro-6 -oxo-3- 6-CN-129 pyridazinyloxy [(-) - enantiomer] 20 164-167 OH 1,6-dihydro-1-ethyl-6-CN-127 6-oxo-3-pyridazinyloxy 206-208 OH 1,6-dihydro-1-methyl-6-CN-124 6-oxo-3-pyridazinyl-25-hydroxy (racemic) 255-256 OH 6-hydroxy-3-pyridaz-6-CN-117 sinyloxy 224-226 OH 2-hydroxy-4-pyridyl-6-NO 2 - 117 oxy 309 24-249.5 OH 2-hydroxy-4-pyridyl-6-CN-104; yloxy * 210-212 OAc 6-hydroxy-3-pyridaz-6-CN-97 sinyloxy 202-203 OH 1,2-dihydro-1-methyl-6-CN - 83 35 2-oxo-4-pyridyloxy> 260 OH 6-hydroxy-3-pyridate-6-NO 2 - 78 sinyloxy 251-252 OH 2-hydroxy-4-pyridyl-6-C00Me - 34 hydroxy • 40 256-258 OH 2-hydroxy-5-pyridyl-6-CN - 23 solution 103-105 OH pyrazinyloxy 6-CN - 21 101-103 OH 2-pyridylthio 6-CN - 18 • · ·

II

92825 15

In the following examples, "ordinary work-up" means: if necessary, adding water, extracting as an organic solvent such as ethyl acetate, separating, drying the organic phase over sodium sulfate, filtering, evaporating to dryness and purifying by chromatography and / or crystallization.

[a] = [a] p ° in methanol.

Example 1

A mixture of 20.1 g of 2,2-dimethyl-3,4-epoxy-10 6-cyanochroman ("IIa"), 14 g of 2-hydroxypyridine (1H-2-pyridone), 7 ml of pyridine and 70 ml of ethanol , boil for two hours. Cool, filter, concentrate the filtrate and chromatograph the residue on silica gel. A mixture of diethyl ether / ethyl acetate (1: 1) gives 2,2-dimethyl-4- (2-pyridyloxy) -6-cyano-3-chromanol, m.p. 102-103 ° C.

In a similar manner (boiling times up to 15 hours) are obtained: 2,2-tetramethylene-4- (2-pyridyloxy) -6-cyano-3-chromanol, m.p. 126-127 ° C, 2,2-pentamethylene-4- (2-pyridyloxy) -6-cyano-3-chromanol, m.p. 108-110 ° C, 2,2-dimethyl-4- (2-pyridyloxy) -6-nitro-3-chromanol, 2,2-dimethyl-4- (2-pyridyloxy) -6-methoxycarbonyl-3-chromanol, 2,2-dimethyl -4- (3-pyridyloxy) -6-cyano-3-chromanol, m.p. 202-204 ° C, 2,2-dimethyl-4- (4-pyridyloxy) -6-cyano-3-chromanol, m.p. 193-196 ° C, 2,2-dimethyl-4- (3-pyridazinyloxy) -6-cyano-3-chromanol, 2,2-dimethyl-4- (2-pyrazinyloxy) -6-cyano-3-chromano -lia, sp. 103-105 ° C.

Example 2 A mixture of 20.1 g of IIa, 11.1 g of 2,4-dihydroxypyridine, 8 ml of pyridine and 400 ml of ethanol is boiled for 15 hours. Evaporate to dryness, extract with ethyl acetate, wash the organic phase with dilute hydrochloric acid, then with water, dry, evaporate to dryness to give 2,2-dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-5 cyano-3-chromanol ("A "), sp. 249-249.5 ° C (from ethanol).

In a similar manner with 2,4-dihydroxypyridine: 2,2-tetramethylene-4- (2-hydroxy-4-pyridyloxy) -6-cyano-3-chromanol, 2,2-pentamethylene-4- (2-hydroxy-4- pyridyloxy) -6-cyano-3-chromanol, 2,2-dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-nitro-3-chromanol, m.p. 224-226 ° C, 2,2-dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-methoxycarbonyl-3-chromanol, m.p. 251-252 ° C; With 2,3-dihydroxypyridine: 2,2-dimethyl-4- (2-hydroxy-3-pyridyloxy) -6-cyano-3-chromanol, m.p. 262-265 ° C; With 2,5-dihydroxypyridine: 2,2-dimethyl-4- (2-hydroxy-5-pyridyloxy) -6-cyano-3-chromanol, m.p. 256-258 ° C; With 3,6-dihydroxypyridazine: 2,2-dimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-cyano-·. 25 ni-3-chromanol ("B"), m.p. 255-256 ° C, 2,2-tetramethylene-4- (6-hydroxy-3-pyridazinyloxy) -6-cyano-3-chromanol, 2,2-pentamethylene-4- (6-hydroxy-3-pyridazinyloxy) -6-cyano- 3-chromanol, m.p. up to 275 ° C, 2,2-dimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-nitro-3-chromanol, m.p. 260 ° C To C, 2,2-dimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-bromo-3-chromanol, m.p. 257-259 ° C, 2,2-dimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-methoxycarbonyl-3-chromanol, m.p. 242 eC.

• · I

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17 92825

Example 3

A mixture of 20.1 g of IIa, 11.1 g of 2-mercapto-pyridine, 6.6 ml of pyridine and 265 ml of ethanol is boiled for three hours. Evaporate to dryness and the resulting 2,2-dimethyl-4- (2-pyridylthio) -6-cyano-3-chromanol is crystallized from diisopropyl ether, m.p. 101-103 ° C.

In a similar manner there are obtained: 2,2-dimethyl-4- (3-pyridylthio) -6-cyano-3-chromanol, 2,2-dimethyl-4- (4-pyridylthio) -6-cyano-3-chromanol, 2,2-dimethyl -4- (2-hydroxy-4-pyridylthio) -6-cyano-3-chromanol, 2,2-dimethyl-4- (6-hydroxy-3-pyridazinylthio) -6-cyano-3-chromanol.

Example 4 A mixture of 2 g of IIa, 1.11 g of 2-mercaptopyridine, 60 ml of DMSO and 0.3 g of NaH (80%) is stirred for six hours at 20 ° C. and further processed in the usual manner. 2,2-Dimethyl-4- (2-pyridylthio) -6-cyano-3-chromene is obtained, m.p. 110-112 ° C.

In a similar manner there are obtained: 2,2-dimethyl-4- (3-pyridylthio) -6-cyano-3-chromene, 2,2-dimethyl-4- (4-pyridylthio) -6-cyano-3-chromene, 2,2-dimethyl-4 - (2-hydroxy-4-pyridylthio) -6-cyano-3-chromene,: 2,2-dimethyl-4- (6-hydroxy-3-pyridazinylthio) -6-cyano-3-chromene.

Example 5

To a solution of 2.66 g of 2,2-dimethyl-4-bromo-6-cyanochroman (m.p. 89-92 ° C; obtained by reduction of 2,2-dimethyl-6-cyano-4-chromanone with NaBH 4 in CH 3 OH to oily 2,2-dimethyl-6-cyano-4-chromanol and react with PBr3 in toluene at 20 ° C) and 2.5 g of pyridazine-3,6-diol in 70 ml of DMSO , 1.2 g of 80% NaH are added and the mixture is stirred for three days at 35 [deg.] C. After the usual work-up, 2,2-18,92825 dimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-cyanochromane are obtained, m.p. 221-224 ° C.

In a similar manner there are obtained: 2,2-dimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-nitro-chromane, 2,2-dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-cyano-chromane, 2.2 - dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-nitrochroman.

10 Example 6

A mixture of 10 g of 2,2-dimethyl-4- (2-pyridylthio) -6-cyano-3-chromanol, 3 g of sodium hydroxide and 350 ml of dioxane is boiled for 20 minutes. Cool, filter, evaporate the filtrate to dryness to give 2.2-15 dimethyl-4- (2-pyridylthio) -6-cyano-3-chromene, m.p.

110-112 ° C.

Example 7

A mixture of 1 g of "B" and 5 ml of acetic anhydride is boiled for one hour. Cool, work up in the usual manner to give 2,2-dimethyl-3-acetoxy-4- (6-hydroxy-3-pyridazinyloxy) -6-cyanochroman, m.p. 210-212 ° C.

In a similar manner there are obtained: 2,2-dimethyl-3-acetoxy-4- (2-hydroxy-4-pyridyloxy) -: 6-cyanochromane.

Example 8

A mixture of 312 mg of "A", 20 ml of acetone, 400 mg of K 2 CO 3 and 0.2 ml of dimethyl sulphate is boiled for two hours. Filter, evaporate to dryness and chromatograph on silica gel. Ethyl acetate / methanol (9: 1) gives 2,2-dimethyl-4- (1,2-dihydro-1-methyl-2-oxo-4-pyridyloxy) -6-cyano-3-chromanol, m.p. 202-203 ° C.

In a similar manner there are obtained: 2,2-dimethyl-4- (1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy) -6-cyano-3-chromanol, m.p. 206-208 ° C,

II

92825 19 2,2-Dimethyl-4- (1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy) -6-nitro-3-chromanol, 2,2-dimethyl-4- (1,2-dihydro -1-ethyl-2-oxo-4-pyridyloxy) -6-cyano-3-chromanol, 5,2-dimethyl-4- (1,2-dihydro-1-ethyl-6-oxo-3- pyridazinyloxy) -6-cyano-3-chromanol, m.p. 164-167 ° C. Example 9

According to Example 8, "B" and 2-bromopropane give 2,2-dimethyl-4- (1,6-dihydro-1-isopropyl-10 6-oxo-3-pyridazinyloxy) -6-cyano-3- chromanolia, sp.

201-203 ° C.

Example 10 a) A mixture of 5 g of "B", 5 g of (+) - camphor-10-sulfonic acid chloride and 50 ml of pyridine is heated for 15 hours at 70 ° C. Work-up with dilute hydrochloric acid and ethyl acetate as usual, chromatograph on silica gel with dichloromethane-ethyl acetate to give the two epimers of "B" - (+) - camphor-10-sulfonic acid ester, m.p. 223-204 ° C and m.p. 127-150 ° C.

b) A mixture of 2 g of "non-polar" epimer (m.p. 223-224 ° C), 16 g of "sodium hydroxide on a carrier" (E. Merck, Katalog "Reagenzien, Diagnostica, Chemikalien", 1987/88, page 587, no. 1567) and 80 ml of methanol, stirred; 25 hours at 20 eC. Evaporate to dryness, dissolve in water, add HCl until pH 8, and filter off the resulting 2,2-dimethyl-4- (1,6-dihydro-6-oxo-3-pyridazinyloxy) -6-cyano-3-chromene (m.p. 226 - 228 ° C). Further treatment of the filtrate at pH 4 with hydrochloric acid / ethyl acetate and chromatography on silica gel with dichloromethane / ethyl acetate / methanol gives (-) - 2,2-dimethyl-4- (1,6-dihydro-6-oxo-3-pyridazinyl). -oxy) -6-cyano-3-chromanol, m.p. 229 ° C; [α] -168.5 °.

c) In a similar manner, (+) - 2,2-dimethyl-4- (1,6-dihydro-92825-20 6-oxo-3-pyridazinyloxy) is obtained from the "polar" epimer-35 (m.p. 127-150 ° C). -6-cyano-3-chromanol, m.p. 232-233 ° C; [α] + 170.0 °.

In a similar manner, 2,2-dimethyl-4- (2-hydroxy-5S-4-pyridyloxy) -6-cyano-3-chromene is obtained from "A" via the corresponding (+) - camphorsulfonic acid esters (m.p. 263- 264 ° C) and (-) - and (+) - 2,2-dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-cyano-3-chromanol.

In a similar manner, 2,2-dimethyl-4- (1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy) -6-cyano-3-Kro-10 manole are obtained via the corresponding (+) - camphorsulfonic acid esters. 2,2-dimethyl-4- (1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy) -6-cyano-3-chromene (m.p. 144-146 ° C) and (-) -2,2-dimethyl-4R- (1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy) -6-cyano-3S-chromanol (m.p. 164 ° C; 15 [a] -165, 1 °) and (+) - 2,2-dimethyl-4S- (1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy) -6-cyano-3R-chromanol (m.p. 161- 162 ° C; [α] + 171.8 °).

The following examples relate to pharmaceutical preparations containing compounds of the formula I or their physiologically acceptable salts:

Example A

tablets

Mixture of 1 g of 2,2-dimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-cyano-3-chromanol, 4 kg of lactose. 25, 1.2 kg of potato starch, 0.2 g of talc and 0.1 g of magnesium stearate are compressed into tablets in the usual manner, each tablet containing 0.1 mg of active ingredient.

Example B 30 Medicinal granules

According to Example A, tablets are compressed, which are then coated in the usual manner with a coating containing sucrose, potato starch, talc, tragacanth and colorant.

• · 92825 21

Example C

Capsules 1 kg of 2,2,3-trimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-cyano-3-chromanol are filled in the usual manner into 5 hard gelatine capsules so that each capsule contains 0.5 mg of active ingredient.

Example D

The ampoules

A solution of 10 g of 2,2-dimethyl-4- (6-hydroxy-10 3-pyridazinyloxy) -6-cyano-3-chromanol in 70 liters of 1,2-propanediol is made up to 100 liters with double-distilled water, filtered sterile, filled into ampoules and sealed sterile. Each ampoule contains 0.1 mg of active substance.

In a similar manner, tablets, granules, capsules or ampoules containing one or more other active compounds of the formula I and / or their physiologically acceptable salts can be obtained.

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Claims (4)

A process for the preparation of therapeutically usable chromane derivatives of formula (I) R 1 where each of R 1 and R 2 are independently A, R 1 and R 2 together may also be an alkylene having 3 to 6 carbon atoms, R 3 is OH or O-COA, R 4 is H, R 3 and R 4 together also represent a bond, R 5 is an unsubstituted or with an A or OH group substituted pyridyl, pyridazinyl, pyrazinyl, oxodihydhydro ropyridyl or oxodihydropyridazinyl radical, R6 is A00C, NO2 or CN, R7 and R8 are hydrogen and z is 0 or S and A is an alkyl of 1-4 carbon atoms, and pharmaceutically acceptable. Removable acid addition salts thereof, characterized in that a chroman of the formula II R 7 wherein XY represents a group -CH-CR8- or CHE-CR3R8- and E is Cl, Br, I or a reactable esterified OH group And the symbols R1, R2, R3, R6, R7 and R8 have, in connection with the formula I given meanings, to react with a compound of formula III R5-ZH III wherein R5 and Z are in the context of the formula I given meanings, or with any reactive derivative thereof, and / or the compound of formula I, wherein R3 Sr OH 10 and R4 Sr H are dehydrated, and / or in the compound of Formula I, a hydroxy group is acylated, and / or in the compound of Formula I, a secondary quaternary atom is alkylated in a heterocyclic ring, and / or a basic compound of Formula I is converted to its pharmaceutically acceptable acid addition salt by treatment with an acid. A process according to claim 1, characterized in that 2,2-dimethyl-4- (2-hydroxy-3-pyridyloxy) -6-cyano-3-chromanol is prepared. 3. A process according to claim 1, characterized in that 2,2-dimethyl-4- (6-hydroxy-3-pyridatine zinyloxy) -6-cyano-3-chromanol is prepared. 4. A process according to claim 1, characterized in that 2,2-dimethyl-4- (1,6-dihydro-1-methyl-6-oxo-3-pyridatzinyloxy) -6-cyano-3-chromanol is prepared. .